UMLS:C0243026 - FACTA Search

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Query: UMLS:C0243026 (sepsis)
52,417 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tumor necrosis factors (TNF) alpha and beta are structurally related cytokines that mediate a wide range of immunological, inflammatory, and cytotoxic effects. During bacterial infection of the bloodstream (sepsis), TNF-alpha induction by bacterial endotoxin is thought to be a major factor contributing to the cardiovascular collapse and critical organ failure that can develop. Despite antibiotic therapy, these consequences of sepsis continue to have a high mortality rate in humans. Here we describe a potent TNF antagonist, a TNF receptor (TNFR) immunoadhesin, constructed by gene fusion of the extracellular portion of human type 1 TNFR with the constant domains of human IgG heavy chain (TNFR-IgG). When expressed in transfected human cells, TNFR-IgG is secreted as a disulfide-bonded homodimer. Purified TNFR-IgG binds to both TNF-alpha and TNF-beta and exhibits 6- to 8-fold higher affinity for TNF-alpha than cell surface or soluble TNF receptors. In vitro, TNFR-IgG blocks completely the cytolytic effect of TNF-alpha or TNF-beta on actinomycin D-treated cells and is markedly more efficient than soluble TNFR (24-fold) or monoclonal anti-TNF-alpha antibodies (4-fold) in inhibiting TNF-alpha. In vitro, TNFR-IgG prevents endotoxin-induced lethality in mice when given 0.5 hr prior to endotoxin and provides significant protection when given up to 1 hr after endotoxin challenge. These results confirm the importance of TNF-alpha in the pathogenesis of septic shock and suggest a clinical potential for TNFR-IgG as a preventive and therapeutic treatment in sepsis.
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PMID:Protection against endotoxic shock by a tumor necrosis factor receptor immunoadhesin. 166 Jan 40

Tumor necrosis factor (TNF) may be involved in the pathogenesis of acute lung injury (ALI) associated with septicemia. Therefore, we measured plasma TNF activity during sepsis and development of lung injury in a porcine model of ALI. Plasma samples were obtained from anesthetized saline-infused control pigs (n = 10) and those infused for 1 h with live Pseudomonas aeruginosa (10(8) organisms/ml, 0.3 ml/20 kg/min) (n = 16). TNF activity was measured in plasma using the L929 fibroblast cytolytic assay. L929 cytotoxicity caused by TNF-alpha or TNF-beta was determined in plasma by measuring the cytotoxicity neutralized by TNF antisera. No significant TNF activity was detected in control pig plasma. In septic pigs, TNF activity appeared in plasma 15 min after onset of septicemia and remained elevated throughout the experiment (6.1 +/- 10.2% to 80.0 +/- 5.0%, 15 and 300 min, respectively). The appearance of pulmonary arterial hypertension, increased lung water, decreased lung compliance, and deteriorating gas exchange was correlated with the rise in plasma TNF activity, which reached a peak at 90 to 120 min in septic pigs. Our results provide evidence that both TNF subtypes are present in plasma during septicemia. Anti-TNF-alpha and anti-TNF-beta neutralized TNF activity in whole septic plasma at 15, 30, and 45 min after onset of septicemia, and the antibodies blocked TNF activity in serially diluted septic plasma at all time points up to 210 min of sepsis. TNF activity in septic plasma at 210 to 300 min was not neutralized entirely by TNF antisera.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Tumor necrosis factor. Alpha and beta subtypes appear in circulation during onset of sepsis-induced lung injury. 202 17

Single daily injections of recombinant human interleukin-1 alpha (IL-1 alpha) or interleukin-1 beta (IL-1 beta) were given for 1-3 days to normal mice, and blood ionized calcium concentrations were measured before and at various times after each injection. Mean blood calcium levels fell significantly in both groups of animals 3 h after the first IL-1 injections and returned to pretreatment values at 5 h. However, at 24 and 48 h mean values were significantly higher than those in saline-heated controls. Despite this progressive underlying increase in mean blood ionized calcium concentrations, blood calcium concentrations also fell significantly 3 h after the second and third IL-1 injections. The transient decrease in blood calcium was prevented by treatment with indomethacin and, thus, appears to be prostaglandin mediated. Hypocalcemia was not observed after single bolus injections of tumor necrosis factor-alpha or -beta (lymphotoxin). These findings suggest that IL-1 is a potential mediator of the hypocalcemia that occurs in up to 40% of patients with bacteremic sepsis and severe tissue injury and is associated with an increased mortality rate.
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PMID:Bolus injections of recombinant human interleukin-1 cause transient hypocalcemia in normal mice. 279 8

The role of IFN-gamma in the regulation of host resistance of Staphylococcus aureus was studied using IFN-gamma receptor-deficient (IFN-gamma R-/-) mice in a model of S. aureus-induced septicemia and arthritis. IFN-gamma R-/- mice and wild-type controls were inoculated intravenously with a toxic shock syndrome toxin-1-producing S. aureus LS-1 strain. IFN-gamma R-/- mice displayed significantly more frequent and more severe arthritis compared with wild-type littermates (p < 0.01) throughout the course of infection. Notably, IFN-gamma R-/- mice developed severe sepsis with high mortality early after the inoculation with staphylococci. However, the mortality of wild-type mice became significantly higher at later stages of the disease compared with IFN-gamma R-/- mice (p < 0.05). This differential outcome of sepsis-related mortality was associated with deficiencies of bacterial elimination from blood and parenchymatous organs and correlated well to serum levels of IL-6 and spleen IL-1 beta and TNF-beta mRNA expression. Thus, bacterial growth and proinflammatory cytokines IL-1 beta, TNF-beta, and IL-6 were higher at the early stage of infection in IFN-gamma-/- mice but increased at the later stage in wild-type littermates. Our data indicate that the absence of IFN-gamma R leads to harmful as well as beneficial effects in S. aureus infection, depending on the stage of the disease and the localization of the infection.
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PMID:Impact of interferon-gamma receptor deficiency on experimental Staphylococcus aureus septicemia and arthritis. 749 61

The vascular endothelium plays a central role in the regulation of extrinsic fibrinolysis and thus maintains vascular patency through clot dissolution. Plasminogen activation provides an important source of localized proteolytic activity not only during fibrinolysis but also during a variety of other physiological and pathological processes. Numerous studies have indicated that human endothelial cells can directly synthesize and secrete plasminogen activators (PA) and inhibitors of these activators. PAs specifically hydrolyse a single arginine-valine bond in plasminogen, an abundant and widely distributed plasma zymogen, to form the broad spectrum serine protease, plasmin. Tissue type-PA (t-PA) and urokinase type PA (u-PA) forms of PA have been described in endothelial cells, although t-PA production and secretion is elevated most frequently. The tPA form of PA functions predominantly in endothelial cell mediated fibrinolysis, while uPA is involved in tissue remodeling. During inflammatory reactions activated mononuclear phagocytes produce a variety of cytokines which may influence the phenotype of the endothelium through a process termed "endothelial cell activation". Tumor necrosis factor alpha (TNF alpha), a mononuclear cytokine, is a distinct polypeptide of Mr 17,000 and has been implicated as a mediator of gram negative induced sepsis as well as angiogenesis. TNF alpha is known to interact with specific endothelial cell receptors and to alter endothelial coagulant and anticoagulant properties implying that cytokines may be potent modulators of hemostasis. Recent observations have indicated that TNF alpha and lymphotoxin (TNF beta) can promote the expression, synthesis and secretion of urokinase plasminogen activator (uPA) in human endothelial cells. The upregulation of uPA results in an alteration in the fibrinolytic capacity of endothelial cells and allows cells the selective ability to degrade and invade underlying subendothelial extracellular matrix (ECM). Endothelial cells treated with TNF alpha also display, in an in vitro angiogenic assay, the ability to invade Matrigel and reorganize into tube-like structures, unlike control cultures. The effects of TNF alpha on the PA proteolytic system of endothelial cells, the biological significance of this event and potential in vivo consequences will be discussed. In addition, the influence of cytokine regulatory control systems will be described, since it is becoming increasingly clear that cytokines do not act in isolation. The vascular endothelium serves as a widely distributed anatomical interface between the blood and tissue with diverse capabilities, performing distinctive biologic functions at different sites and within specific organs.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Cytokine regulation of endothelial cell extracellular proteolysis. 835 23

Tumor necrosis factor (TNF) is recognized as a central mediator of sepsis, septic shock, and multiple organ failure. These host reactions are associated with increased TNF levels in circulation, presumably due to increased TNF production. A previously described nucleotide variation at position -308 in the promoter region of the human TNF gene was shown to be associated with the clinical outcome of malaria. In this study we addressed the relevance of the -308 polymorphism for expression of the human TNF gene in response to bacterial endo- toxin in vivo and in vitro. First, we typed 80 patients suffering from severe sepsis and 153 healthy individuals and found no association of the -308 variation with incidence of the disease. In contrast, the NcoI marker in the closely linked lymphotoxin-alpha (LT-alpha) gene showed association with survivaL This discrepancy can be explained by the linkage of the TNFB2(NcoI) allele to the common TNF1 (-308) allele. Second, we generated reporter gene constructs with the promoter deletions and with both -308 variation in the context of the extended human TNF promoter region. Although such constructs were highly inducible by lipopolysaccharide (LPS) in transient transfections into a macrophage cell line, the -308 variation had no significant effect on transcription, consistent with the promoter deletion study. We conclude that the functional consequence of the -308 polymorphism may be unrelated to transcriptional response of the TNF gene to bacterial endotoxin.
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PMID:-308 tumor necrosis factor (TNF) polymorphism is not associated with survival in severe sepsis and is unrelated to lipopolysaccharide inducibility of the human TNF promoter. 883 66

T cell release of lymphotoxin-alpha (LT-alpha, or TNF-beta) is stimulated by pyrogenic exotoxins of Gram-positive bacteria and mitogens. In contrast to TNF-alpha, it is unknown whether LT-alpha plays any role in the pathogenesis of sepsis and, in particular, the pathogenesis of Gram-positive sepsis. Sera from patients with sepsis were examined for LT-alpha and compared with normal volunteers and pregnant women. LT-alpha was detected in 33% of sepsis sera (mean 608.4 pg/ml SE 306), 16% of normal sera (mean 167 pg/ml SE 87) and 23% of sera from pregnant women (mean 714 pg/ml SE 191). These differences were not significant and there were no differences within sepsis sera when grouped by the type of causative organism, or disease severity. LT-alpha detected by immunoassay in serum was not bioactive, in contrast to that produced in cell culture. Recombinant soluble TNF receptors (rSTNFR) neutralized the bioactivity of recombinant LT-alpha at rSTNFR concentrations which did not interfere with immunoreactivity and which are known to prevail in vivo. Hence, LT-alpha is unlikely to have a critical role in the pathogenesis of sepsis. Much of the potential bioactivity of this lymphokine may be abrogated by TNFR in serum.
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PMID:Lymphotoxin-alpha (TNF-beta) during sepsis. 905 Jul 52

To evaluate the importance of the proinflammatory cytokines TNF and lymphotoxin-alpha (LT alpha) in an experimental model of Staphylococcus aureus sepsis and arthritis, we used TNF/LT alpha-double-deficient mice raised on the C57BL/6 background. Mice were i.v. inoculated with a toxic shock syndrome toxin-1 (TSST-1)-producing S. aureus strain, LS-1. Intravenous inoculation of a high dose of bacteria (1 x 10(7)/mouse) resulted in 67% mortality in TNF/LT alpha-deficient mice, whereas none of the controls died (p = 0.009). Those results correlated to a significantly decreased phagocytosis in vitro and inefficient bacterial clearance in vivo in mice lacking capacity to produce TNF/LT alpha. Thus, at day 6 after inoculation, S. aureus could not be found in the bloodstream of controls, but bacteremia developed in all TNF/LT alpha-deficient mice examined (p = 0.02). Interestingly, upon infection with a lower dose of staphylococci (3 x 10(6)/mouse) the mortality was overall low, but the frequency of arthritis was clearly higher in the wild-type group as compared with the TNF/LT alpha-deficient mice (40% vs 13%). Histopathologic examination revealed a lower frequency of synovitis (38% vs 90%, p < 0.05) and erosivity (25% vs 60%, NS) in TNF/LT alpha-deficient mice as compared with wild-type counterparts. Our results show the importance of TNF/LT alpha in defense against systemic S. aureus infections and point out the detrimental role of these cytokines as mediators of inflammatory response in S. aureus arthritis.
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PMID:TNF/lymphotoxin-alpha double-mutant mice resist septic arthritis but display increased mortality in response to Staphylococcus aureus. 983 74

Explosion of knowledge both in human genomics and in host inflammatory response explains the increasing interest in infectious disease genetics over the last 5 years. However, twin and adoptee studies have suggested more than 15 years ago, that host genetic factors are major determinants of susceptibility to infectious diseases in humans. Recently, candidate gene studies (association studies) and human genomewide analysis have been used to identify infectious diseases susceptibility and resistance genes. Rarely, a single gene defect has been directly related to devastating consequences such as interferon-gamma receptor mutations leading to fatal infections with ubiquitous mycobacteria. For clinical practice, gene polymorphisms of specific host immune defence elements appear to be of major importance. These genetic variants, which modify the regulation or function of the mediators, have been associated with susceptibility and/or outcome of severe sepsis and septic shock. All steps of the host response to bacteria may be affected by genetic factors. For example, Fc gamma receptor, Toll like receptor or mannose binding protein mutations have been shown to modify the detection of pathogens leading to pneumococcal severe infections, Gram-negative bacteria septic shock, and meningococcal disease, respectively. Polymorphisms of cytokine genes (TNF-alpha, TNF-beta, IL-1-ra) have been reported to influence the level of secreted mediators and to unbalance the inflammatory cascade. Coagulation response to sepsis may also be affected by gene variants such as the plaminogen activator inhibitor 1 (PAI-1) common functional polymorphism which increases the risk of death from meningococcal infection or severe trauma. The impact of these findings on the understanding of infectious disease pathogenesis and on the design of future preventive and therapeutic strategies should be considerable.
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PMID:[Role of host response during severe bacterial infection]. 1158 14

Pseudomonas aeruginosa infection, one of the major complications of burn wounds, may lead to sepsis and death. Using the Multi-Probe Template/RNase protection assay, we have compared the expression of different cytokine genes within the skin and livers of thermally injured mice infected with P. aeruginosa PAO1. Thermal injury alone enhanced or up-regulated certain cytokines, including macrophage colony-stimulating factor (M-CSF), interleukin 1 (IL-1)RI, IL-1 beta, macrophage inflammatory protein (MIP)-1 beta and MIP-2; while PAO1 challenge alone up-regulated tumour necrosis factor alpha (TNF-alpha) and transforming growth factor beta (TGF-beta) expression. The combination of thermal injury plus PAO1 infection enhanced the expression of several pro-inflammatory and haematopoietic cytokines [stem cell factor (SCF), leukocyte inhibitory factor (LIF), IL-6 and TNF-alpha]; induced the expression of granulocyte-macrophage colony-stimulating factor (GM-CSF) and G-CSF by 5 h and the expression of additional cytokines, including TGF-beta, TNF-beta, lymphotoxin beta (LT-beta), interferon gamma (IFN-gamma), and IFN-beta by 40 h post-burn/infection. While the most intense cytokine expression occurred in the skin, the majority of cytokines tested were also expressed in the liver by 40 h post-burn/infection. These results suggest that in P. aeruginosa infection of burn wounds: (1) up-regulation of the expression of different cytokines, locally and within the livers of burned mice, is an indication of P. aeruginosa -induced sepsis; and (2) IL-6 and G-CSF play an important role in the host response mechanism.
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PMID:The effects of infection of thermal injury by Pseudomonas aeruginosa PAO1 on the murine cytokine response. 1179 26

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